Hemangiosarcoma (HSA) is a form of cancer originating in the endothelium, which is the lining of the heart, blood vessels, lymphatics, and spleen. HSAs have a predilection for the heart, pericardium and spleen. Due to their presence in internal organs, primary tumors are difficult to detect prior to the manifestation of clinical disease.
The direct cause of death due to HSA is disseminated intravascular coagulation, which causes the mammal to exhibit platelet deficiency, increased blood clotting times, decreased blood fibrin content, and increased fibrin degradation products. At present, there is no successful chemotherapeutic or radiation protocol for treatment of hemangiosarcoma (Clifford et al., J. Vet. Intern Med. 2000, 5:479). The average post-splenectomy survival time has been reported to be 49-120 days in canines. In fact, even with surgery and chemotherapy with doxorubicin, prognosis is less than six month once diagnosed in canines (Sorenmo et al., J Vet Intern Med 2000, 14(4):392-4).
A histone deacetylase inhibitor, such as SAHA (Richon et al., Proc. Natl. Acad. Sci. USA 1998, 95:3003), has been shown in cell culture and animal model studies to act as an anticancer agent (Marks et al., Curr. Opin. Oncol. 2001, 13:477). Subsequently, a series of studies was conducted in the N-nitrosomethylurea (NMU)-induced rat mammary tumor model using SAHA administered in the diet first as a chemopreventive agent and later as a chemotherapeutic agent (Cohen et al., Anticancer Res. 1999, 19: 4999-5006; Cohen et al., Anticancer Res. 2002, 22:1497-1504).
In 1999, it was found for the first time that SAHA could significantly inhibit the time of appearance, incidence, multiplicity and total number of NMU-induced rat mammary tumors, when added to the diet, with no deleterious side effects (Cohen et al., 1999). This was the first demonstration that SAHA could act as a chemopreventive agent in a solid (non-hematopoeitic) rat tumor. Further investigation showed that the presence of SAHA was required throughout the study period (Cohen et al., 2002). SAHA administered in the diet was found to decrease the size, slow the growth rate and, in some cases, induce the complete regression of established rat mammary tumors, again with no toxic side effects (Cohen et al., 2002). In addition, Butler et al. (Cancer Res. 2000, 60:5165) demonstrated that SAHA inhibited tumor growth of human prostate cancer cells in the mouse xenograft model.
Nonetheless, the data are not predictive for canines. Many cancers remain untreatable, and therapeutic approaches effective in one cancer often fail in another. Thus, there is a need in the art to treat certain aggressive forms of cancer and cancers that evade surveillance, and a need to adapt new therapies to treating otherwise untreatable tumors.